Injectable local anesthetic solutions comprising mixtures of soluble procaine and butethamine salts



latory effects.

iNiEcTAnLE LOCAL ANEs'rHErrc SOLUTION COMPRISING Mrxruans or SOLUBLE Pao- CAlNE AND BUTETHAMENE SALTS Samuel D. Goldberg, West Hempstead, N. Y.

No Drawing Application October s, 1955 Serial No. 538,274

11 Claims. (Cl. 167--52) This invention relates, generally, to compositions of 5 matter useful in medicine and, more particularly, it .relates to certain novel compositions useful for producing local anesthesia.

It is known that certain chemical substances, when applied or administered parenterally to the human body, are capable of blocking nerve conduction from the area or region of application or administration and this thus limited blocking eifect is known as local or regional anesthesia. Local anesthesia produced by parenterally administrable substances is designated according to the o technique employed or the anatomic site of administration: Infiltration anesthesia is injection directly into the area. which is painful or to be subjected to surgical trauma; conductive or nerve block anesthesia is injection in proximity to specific nerve trunks supplying a particular anatomic site.

All local anesthetic agents are toxic and the tolerance of individuals varies. Safe dosage is therefore limited for each drug, and administration must be individualized. The choice of the drug to be used, its concentration, rate and location of administration, mode of administration, along with the individuals age, emotional and physical status are a few of the factors involved. Great care must vbe exercised in parenteral administration of local anesthetics to assure that merely subcutaneous, not intravenous, administration is eifected because these substances have profound toxic reactions when administered intravenously. In general, the smallest amount of the least toxic drug that will serve the intended purpos should be employed.

Of the group of local anesthetic agents suitable for parenteral administration, probably the most widely used is the substance procaine, usually in the form of an isotonic saline solution of procaine hydrochloride at a concentration of about 2% by weight, i. e., the solution contains, in each one hundred cubic centimeters, not less than 1.9 grams and not more than 2.1 grams of procaine hydrochloride. Solutions containing greater or lesser concentrations of procaine hydrochloride, and solutions of other procaine salts, such as the borate, which is readily water soluble, and the butyrate, which is soluble both in water and in vegetable oils, have been found satisfactory for use as local anesthetics. Procaine anesthetics, when administered subcutaneously, induce anesthesia approximately equal to thatv produced by cocaine, While being a mere fraction as toxic as cocaine and virtually free from untoward respiratory and circu- The chief disadvantage of procaine anesthetics is that the anesthesia, although rapidly induced, also rapidly disappears; it has been reported that within two minutes following injection, only faint traces of procaine can be found in the blood. This disadvantage, to a limited degree, may be overcome by simultaneous administration of a vasoconstrictor, such as epinephrine, which effectively prolongs the anesthetic effect.

Another substancethat has been found useful as a local anesthetic to be administered by subcutaneous injection procaine hydrochloride solution is of equal effectiveness. However, the improvement in the anesthetic power of butethamine over that of procaine is accompanied by the disadvantage that the toxicity of butethamine, also, is about one third greater than that of procaine. For dental or other minor surgery, a 1.0% by weight solution of butethamine hydrochloride with epinephrine (l:75,000) may be injected to obtain nerve block anesthesia; in major surgery or other procedures requiring nerve block anesthesia equivalent to that produced by 2.0% by Weight procaine solution, a 1.5% by weight solution of butethamine hydrochloridewith epinephrine (l:lO0,000) may be used.

Other anesthetics, such as tetracaine and dibucaine, have the disadvantage that, when administered with epinephrine and in sufficient amounts to produce the desired rapid and profound anesthesia, the anesthesia is very prolonged and reactions due to the toxicity of the anesthetic frequently occur. Moreover, all of the abovementioned anesthetics, when administered subcutaneously, show little tendency to spread into tissues surrounding the situs of administration; hence, the anesthetic eifect is substantially limited to the immediate locality of administration and nerve block anesthesia, rather than infiltration anesthesia, generally must be relied on to achieve the necessary effects.

One of the objects of this invention is to provide cer-' tain novel compositions, suitable for subcutaneous administration to produce local anesthesia, qualitativelyidentical in anesthetic action with procaine and butethamine but having a materially lesser toxicity.

Another object of this invention is to provide local anesthetic agents that, in contrast and comparison with procaine and butethamine preparations heretofore known, are suited for use in infiltration anesthesia and that, when administered subcutaneously, readily and rapidly spread into tissue surrounding the situs of administration, producing profound anesthesia therein.

A further object of this invention is to provide novel local anesthetic compositions of the type aforesaid that are stable, easy to produce, and that can be produced at costs comparable to those of procaine and butethamine preparations now in use.

Other objects of this invention will be apparent as the detailed description of the invention proceeds.

Regarded in certain broader aspects, the novel local anesthetic agents in accordance with this invention are aqueous solutions containing, in synergistic combination, a soluble procaine salt and a soluble butethamine salt,

vso proportionated'that there is present in the mixture,

per unit weight of butethamine, one to three units of weight of procaine. markable in that their toxicity is materially less than that of a solution containing either procaine or butethamine in an amount equal to'the total amount of these substances in the new compositions. For instance, a composition containing two percent by weight of procaine and 1.5 percent by weight of ,butethamine has, at most, about two-thirds the toxicity of a 3.5% by weight procaine solution, and even less than two-thirds the passe June 10, 1958 These novel compositions are retoxicity of a 1.5% by weight solution of butethamine salt. The term synergistic combination is herein used in the special and limited significance that it refers to this unexpected and unpredictable phenomenon whereby two toxic substances so coact, without loss or impairment of their physiological potencies, that the toxicity of the combination is materially less than the aggregated toxicities of the components.

Using white mice as test animals, it is found that the toxicity of procaine hydrochloride, administered subcutaneously in the form of an aqueous solution containing 2.0% by weight of the salt, is 750 milligrams of the salt per kilogram of test animal weight; and, when tested under the same conditions, it is found that the toxicity of butethamine hydrochloride is approximately 550 milligrams of salt per kilogram of test animal weight. These values are the minimum lethal dosages of these drugs, i. e., the minimum amounts of these drugs that, when administered subcutaneously, result in death of the test animal. Likewise, using guinea pigs as thetest animals, it is found that the subcutaneous toxicity of procaine is 410-430 milligrams of procaine hydrochloride per kilogram of test animal body weight; while, under the same test conditions, the minimum lethal dose of butethamine hydrochloride is 210255 milligrams per kilogram.

Under comparable test conditions, it is found that the following compositions according to this invention possess the toxicity indicated:

Minimum lethal dose (M L D50) Using white mice as test animals and subcutaneously administering to them:

(1) Isotonic saline solution containing 2% by weight procaine hydrochloride and 1% by weight of butethamine hydrochloride.

(2) Isotonic saline solution containing 2% by weight of procaine hydrochloride and 1.25% by weight of butethamine hydrochloride (3) Isotonic saline solution containing 2% by weight of procaine hydrochloride and 1.5% by weight of butethamine hydrochloride Using guinea pigs as test animals and subcutaneously administering to them:

(1) Isotonic saline solution containing. 2% by weight of procaine hydrochloride and 1% by weight of butethamine hydrochloride (2) Isotonic saline solution containing 2% by weight of procaine hydrochloride and 1.25% by weight of butethamine hydrochloride (3) Isotonic saline solution containing 2% by weight of grccaine hydrochloride and 1.5% by weight of utethamine hydrochloride JVIqsn/kilo.

From these data, especially the studies conducted with white mice as the test animals, it is evident that the combination of 2% procaine hydrochloride with 1% butethamine hydrochloride, or with 1.25% butethamine hydrochloride, results in a product having a toxicity indistinguishable from that of a 2% procaine solution alone,

although the anesthetic power is increased to that of a 3 /a% procaine solution, or a 3.6% procaine solution, respectively. These results are the more impressive when compared with the toxicity data found by studies of subcutaneous injection of procaine solutions at concentrations higher than 2.0% by weight: using white mice as the test animals, it is found that the minimum lethal dose, using a solution containing 3.0% procaine hydrochloride, is 700 milligrams per kilogram of animal body weight and, using a 4.0% solution, the minimum lethal dose is 550 milligrams per kilogram. This remarkable synergistic action is. limited to combinations of procaine and butethamine, so far as now known, and it is not exhibited in combinations of procaine with other local anesthetics. For example,,which serves further to emphasize the unexpectedncss of this synergistic action, it is found that the addition of merely 0.15% of tetracaine hydrochloride to a 2.0% procaine hydrochloride solution results in a product more'than twice (ca. 2.3 as toxic as the procaine hydrochloride solution alone, the minimum V substantially the same manner as the subcutaneous toxicities above discussed. Using unanesthetized rabbits as test animals, the minimum lethal intravenous dose for procaine is found to be 45 milligrams per kilogram of animal weight; that for butethamine is found to be 32 milligrams per kilogram; whereas compositions according to this invention containing 2.0% by weight procaine hydrochloride and 1.0% to 1.5% by weight of butethamine show minimum lethal dose levels of to 40 milligrams per kilogram of test animal weight.

Compositions embodying the principles of the present invention may be prepared using any of the water soluble salts of procaine and butethamine, the term salts here signifying the products obtained by treating the free amine bases with a mineral or simple, water soluble organic carboxylic acid. Although the hydrochlorides are the presently preferred salts, it will be understood that other salts may be used as above indicated. The ratio of butethamine to procaine salt in these products is one part by weight of the former per one to three parts by weight of the latter. As a practical matter, it seldom is necessary or desirable to use either component at a concentration less than about 0.25% of the total weight of solution; hence, this may be regarded as an eifective minimal concentration for the individual components. Similar considerations set 2.0% of total weight as the effective upper limit of concentration for the butethamine and 6.0% of total weight for the procaine component. The use of butethamine hydrochloride in amounts within the range of 1.0% to 1.5% of total weight, and of procaine hydrochloride in the amount of 2.0% of the total weight of finished solution presently is preferred.

In addition to the improvement in toxicity effected in the novel compositions according to this invention, compared to anesthetic compositions containing the individual components separately, these new compositions have another remarkable property: their ability to migrate into surrounding tissue near the situs of injection. This property is of great importance as it permits the anesthetic to be administered by infiltration rather than restricting its use to block anesthesia as has been necessary with procaine preparations and with butethamine preparations of types heretofore known. This property may be demonstrated by intracutaneous wheal tests on human subjects. In these tests, a small amount of the drug under test is injected below the skin surface between the epidermis and the under-lying tissue, whereby a bleb is produced and the area of this bleb is indicative of the degree of spread of the injected material from the point of injection, and, in this instance, it is indicative of the area of anesthetization. Using a solution containing 1.5% procaine hydrochloride in isotonic saline, no appreciable spreading was observed; using a 1.5% butethamine hydrochloridc solution, the area of spreading was found to be 1.25 centimeters in diameter; and, when epinephrine was included in the butethamine solution, the area of spreading was found to be 1.50 centimeters in diameter. A solution according to the present invention, containing 2.0% by weight procaine hydrochloride and 1.0% to 1.5% by weight of butethamine, but containing no vasoconstrictor, spread over an area 2.0 centimeters in diameter; and, after addition of a vasoconstrictor (epinephrine) to this solution, the area of spread was found to be 3.0 centimeters in diameter.

This property of spreading is of great importance in anesthesia as it permits the anesthetist to induce a rapid and profound anesthesia due to infiltration of the anesthetic throughout the area surrounding the situs of administration. In clinical studies of compositions embodying the principles of this invention, the rate at which anesthesia was established was observed in 500 cases. It was found that complete anesthesia was established immediately following injection over a -30 second period, whereas, in block or conductive anesthesia, the injection requires 45-60 seconds and anesthesia is not established until about one and one-half minutes thereafter.

It is preferred, in compositions embodying the principles of this invention, to include a suitable vascoconstrictive sympathomimetic amine, such as epinephrine, phenylephrine, laevoarterenol and the like, for the purpose of localizing and prolonging the action of the anesthetic. These substances in amounts of less than 0.02% of the total weight of the solution are effective for this purpose. In general, for anesthetics to be used in dentistry, it is preferred to use epinephrine in the proportion of 1:50,000 to 1:100,000 parts by weight; phenylephrine, 1:2,500 to 1:3,500; and laevo-arterenol, 130,000 to 1:60,000. For anesthetics to be used in surgery, it is preferred to use somewhat less of the vascoconstrictor, say, for epinephrine, 1:130,000 to 1:500,000 parts by weight.

It is to be understood that the term butethamine, as herein employed, signifies not only the 2-isobutylaminoethanol ester of para-aminobenzoic acid, but also its isomer, the 2-isobutylaminoethanol ester of meta-aminobenzoic acid, which, too, is a potent local anesthetic. The para-isomer is the preferred member of this group for the purposes of this invention.

To facilitate a fuller and more complete understanding of the principles of this invention and of how the products in accordance therewith best may be made, several specific examples follow, provided by way of illustration merely, not by way of limitation upon the invention defined by the subjoined claims.

EXAMPLE 1 An aqueous solution is prepared containing the follow-' ing substances in substantially the proportions indicated: procaine hydrochloride, 2.0% by weight; p-butethamine hydrochloride, 1.25% by weight; sodium chloride, 0.45%

by weight; sodium bisulfite, 0.02% by weight; methyl para-hydroxybenzoate, 0.01%; and epinephrine, sufiicient to produce a concentration of one part per 75,000 parts by weight of finished solution. The product has the properties hereinabove described.

EXAMPLE 2 A solution is prepared as described in Example 1 except that the proportion of p-butethamine hydrochloride is increased to 1.5% by weight. The product so obtained has the properties hereinabove described.

EXAMPLE 3 present in the mixture, per unit weight of butethamine, one to three units of weight of procaine.

2. A new composition of matter as defined in claim 1 wherein the soluble butethamine salt is present in the aqueous solution in an amount Within the range of 0.25% to 2.0% by weight, based on the total weight of the solution.

3. A new composition of matter as defined in claim 1 wherein the soluble butethamine salt is present in the aqueous solution in an amount within the range of 1.0% to 1.5% by weight, based on the total weight of the solution.

4. A new composition of matter as defined in claim 1 wherein the soluble procaine salt is present in the aqueous solution in an amount substantially equal to 2.0% of the total weight of the solution.

5. As a new composition of matter, useful in medicine as a local anesthetic agent, an isotonic aqueous saline solution containing, in synergistic combination, a soluble procaine salt and a soluble butethamine salt, so proportionated that there is present in the solution, per unit weight of butethamine, one to three units of weight of procaine; and a vascoconstrictive sympathomimetic amine in an amount less than 0.02% by weight, based on the total weight of the solution.

6. A new composition of matter as defined in claim 5 wherein the soluble butethamine salt is present in the aqueous saline solution in an amount within the range of 0.25% to 2.0% by weight, based on the total weight of the solution.

7. A new composition of matter as defined in claim 5 wherein the soluble butethamine salt is present in the aqueous saline solution in an amount within the range of 1.0% to 1.5 by weight, based on the total weight of the solution.

8. A new composition of matter as defined in claim 5 wherein the soluble butethamine salt is butethamine hydrochloride, the soluble procaine salt is procaine hydro-' chloride, and the vasoconstrictive sympathomimetic amine is epinephrine.

9. A new composition of matter as defined in claim 8 wherein the butethamine hydrochloride is present in the aqueous saline solution in an amount within the range of 0.25% to 2.0% by weight, based on the total weight of the solution.

10. A new composition of matter as defined in claim 8 wherein the butethamine hydrochloride is present in the aqueous saline solution in an amount within the range of 1.0% to 1.5% by weight, based on the total weight of the solution.

11. A new composition of matter as defined in claim 8 wherein the procaine hydrochloride is present in the aqueous saline solution in an amount substantially equal to 2.0% of the total weight of the solution.

Goodman et al.: Pharmacological Basis of Therapeutics, 2nd ed., 1955, Macmillan Co., New York city, p. 365.

Gray et al., Jour. Pharm. and Pharmacol, February 1954, vol. 6, No. 2, pp. 89-114. 

1. AS A NEW COMPOSITION OF MATTER, USEFUL IN MEDICINE AS A LOCAL ANESTHETIC AGENT, AN AQUEOUS SOLUTION CONTAINING, IN SYNERGISTIC COMBINATION, A SOLUBLE PROCAINE SALT AND A SOLUBLE BUTEHTAMINE SALT, SO PROPORTIONATE THAT THERE IS PRESENT IN THE MIXTURE, PER UNIT WEIGHT OF BUTETHAMINE, ONE TO THREE OF WEIGHT OF PROCAINE. 